Novel and efficient method for the synthesis of an amino acid

Abstract

The present invention relates to a novel process for the preparation of γ-amino acids, such as (±)-3-(aminomethyl)-5-methyl-hexanoic acid (1), which is a key intermediate in the preparation of the potent anticonvulsant pregabalin, (S)-(+)-3-(aminomethyl)-5-methyl-hexanoic acid (2), and its analogues.

1 - 85 . (canceled) 
     
     
         86 . A process for the preparation of a γ-amino acid VI, comprising one or more steps selected from:
 (i) the reaction of carbonyl compound I with nitromethane to form alcohol II: 
 
       
         
           
           
               
               
           
         
       
       and/or
 (ii) the conversion of alcohol II to intermediate IV: 
 
       
         
           
           
               
               
           
         
       
       and/or
 (iii) the conversion of intermediate IV to γ-nitro acid V, followed by the reduction of γ-nitro acid V to γ-amino acid VI: 
 
       
         
           
           
               
               
           
         
         wherein each R is independently an alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl or alkynylaryl group, each of which may optionally be substituted, and each of which may optionally include one or more heteroatoms N, O or S in its carbon skeleton; and 
         wherein R′ and R″ are independently hydrogen or an alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl or alkynylaryl group, each of which may optionally be substituted, and each of which may optionally include one or more heteroatoms N, O or S in its carbon skeleton, or both R′ and R″ together with the carbon atom to which they are attached form a cyclic alkyl or cyclic alkenyl group, each of which may optionally be substituted, and each of which may optionally include one or more heteroatoms N, O or S in its carbon skeleton. 
       
     
     
         87 . A process according to  claim 86 , wherein the process comprises two or three of steps (i) to (iii). 
     
     
         88 . A process according to  claim 86 , wherein:
 (i) each R is independently an alkyl group; and/or   (ii) each R is independently a methyl, ethyl, propyl or butyl group; and/or   (iii) each R is a methyl group; and/or   (iv) the atoms by which both R′ and R″ are attached to the carbonyl group are either hydrogen or carbon; and/or   (v) R′ and R″ are independently hydrogen or an alkyl group, or both R′ and R″ together with the carbon atom to which they are attached form a cyclic alkyl group; and/or   (vi) R′ and R″ are independently hydrogen or a C 1-6  alkyl group, or both R′ and R″ together with the carbon atom to which they are attached form a C 5-7  cyclic alkyl group; and/or   (vii) one of R′ and R″ is hydrogen and the other is i-butyl; and/or   (viii) both R′ and R″ together with the carbon atom to which they are attached form a cyclohexyl group.   
     
     
         89 . A process according to  claim 86 , wherein:
 (i) a carbanion of nitromethane is generated in step (i) with a base; and/or   (ii) a carbanion of nitromethane is generated in step (i) with a base, wherein the base is not an amine; and/or   (iii) a carbanion of nitromethane is generated in step (i) with a hydride, an alkoxide or a hydroxide; and/or   (iv) a carbanion of nitromethane is generated in step (i) with sodium methoxide; and/or   (v) step (i) is carried out in an ether solvent; and/or   (vi) step (i) is carried out in an ether solvent selected from tetrahydrofuran, diisopropyl ether, tert-butyl methyl ether, diethyl ether, or mixtures thereof; and/or   (vii) step (i) is carried out in tetrahydrofuran.   
     
     
         90 . A process according to  claim 86 , wherein the conversion of step (ii) comprises the substitution of the hydroxyl group of alcohol II to give intermediate IIIa: 
       
         
           
           
               
               
           
         
       
       wherein Y is:
 (i) a suitable leaving group; and/or 
 (ii) a halo group; and/or 
 (iii) —Br. 
 
     
     
         91 . A process according to  claim 86 , wherein the conversion of step (ii) comprises the activation of the hydroxyl group of alcohol II to give intermediate IIIb: 
       
         
           
           
               
               
           
         
       
       wherein:
 (i) Z is any group capable of enhancing the capacity of a hydroxyl group as a leaving group; and/or 
 (ii) Z is selected from a —SO 2 R a , —SO 2 OR a , —NO 2 , —COR a , —P(═O)(OR a ) 2  or —B(OR a ) 2  group, wherein each R α  is independently selected from hydrogen, a halogen, or an optionally substituted alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl or arylalkynyl group, and wherein any two R a  groups may together with the atoms to which they are attached form a ring; and/or 
 (iii) Z is selected from a —SO 2 R a , —SO 2 OR a , —NO 2 , —COR a , —P(═O)(OR a ) 2  or —B(OR a ) 2  group, wherein each R a  is independently selected from an alkyl, aryl or arylalkyl group optionally substituted with one or more groups selected from —F, —Cl, —Br or —NO 2 ; and/or 
 (iv) Z is selected from a —SO 2 R a , —SO 2 OR a  or —COR a  group, wherein each R α  is independently selected from hydrogen, a halogen, or an optionally substituted alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl or arylalkynyl group, and wherein any two R a  groups may together with the atoms to which they are attached form a ring; and/or 
 (v) Z is selected from a —SO 2 R a , —SO 2 OR a  or —COR a  group, wherein each R a  is independently selected from an alkyl, aryl or arylalkyl group optionally substituted with one or more groups selected from —F, —Cl, —Br or —NO 2 ; and/or 
 (vi) —OZ is selected from a tosylate, brosylate, nosylate, mesylate, tresylate, nonaflate or triflate group; and/or 
 (vii) Z is a —COR a  group, wherein each R a  is independently selected from hydrogen, a halogen, or an optionally substituted alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl or arylalkynyl group, and wherein any two R a  groups may together with the atoms to which they are attached form a ring; and/or 
 (viii) Z is a —COR a  group, wherein each R a  is independently selected from an alkyl, aryl or arylalkyl group optionally substituted with one or more groups selected from —F, —Cl, —Br or —NO 2 ; and/or 
 (ix) Z is an acetyl or trifluoroacetyl group. 
 
     
     
         92 . A process according to  claim 90 , wherein the conversion of step (ii) further comprises the transformation of intermediate IIIa or of intermediate IIIb into intermediate IV: 
       
         
           
           
               
               
           
         
       
       wherein the transformation is achieved by using:
 (i) a carbanion of CH 2 (CO 2 R) 2 ; and/or 
 (ii) a carbanion of CH 2 (CO 2 R) 2 , wherein the carbanion of CH 2 (CO 2 R) 2  is generated using an alkoxide base, optionally in combination with a metal carbonate; and/or 
 (iii) a carbanion of CH 2 (CO 2 R) 2 , wherein the carbanion of CH 2 (CO 2 R) 2  is generated using an alkoxide base, optionally in combination with sodium carbonate; and/or 
 (iv) a carbanion of CH 2 (CO 2 R) 2 , wherein the carbanion of CH 2 (CO 2 R) 2  is generated using sodium methoxide, optionally in combination with a metal carbonate; and/or 
 (v) a carbanion of CH 2 (CO 2 R) 2 , wherein the carbanion of CH 2 (CO 2 R) 2  is generated using sodium methoxide, optionally in combination with sodium carbonate. 
 
     
     
         93 . A process according to  claim 91 , wherein the conversion of step (ii) further comprises the transformation of intermediate IIIa or of intermediate IIIb into intermediate IV: 
       
         
           
           
               
               
           
         
       
       wherein the transformation is achieved by using:
 (i) a carbanion of CH 2 (CO 2 R) 2 ; and/or 
 (ii) a carbanion of CH 2 (CO 2 R) 2 , wherein the carbanion of CH 2 (CO 2 R) 2  is generated using an alkoxide base, optionally in combination with a metal carbonate; and/or 
 (iii) a carbanion of CH 2 (CO 2 R) 2 , wherein the carbanion of CH 2 (CO 2 R) 2  is generated using an alkoxide base, optionally in combination with sodium carbonate; and/or 
 (iv) a carbanion of CH 2 (CO 2 R) 2 , wherein the carbanion of CH 2 (CO 2 R) 2  is generated using sodium methoxide, optionally in combination with a metal carbonate; and/or 
 (v) a carbanion of CH 2 (CO 2 R) 2 , wherein the carbanion of CH 2 (CO 2 R) 2  is generated using sodium methoxide, optionally in combination with sodium carbonate. 
 
     
     
         94 . A process according to  claim 86 , wherein:
 (i) the conversion of step (iii) of intermediate IV to γ-nitro acid V comprises hydrolysis and decarboxylation; and/or   (ii) the conversion of step (iii) of intermediate IV to γ-nitro acid V comprises hydrolysis and decarboxylation, wherein the hydrolysis and decarboxylation is carried out using an organic or mineral acid in the presence of water; and/or   (iii) the conversion of step (iii) of intermediate IV to γ-nitro acid V comprises hydrolysis and decarboxylation, wherein the hydrolysis and decarboxylation is carried out using hydrochloric acid in the presence of water; and/or   (iv) the reduction of step (iii) of γ-nitro acid V to γ-amino acid VI is performed using catalytic hydrogenation; and/or   (v) the reduction of step (iii) of γ-nitro acid V to γ-amino acid VI is performed using catalytic hydrogenation, wherein the hydrogenation catalyst is selected from Pd/C, Pt/C or PtO 2 ; and/or   (vi) the reduction of step (iii) of γ-nitro acid V to γ-amino acid VI is performed using catalytic hydrogenation, wherein the hydrogenation catalyst is Pd/C.   
     
     
         95 . A process according to  claim 86 , wherein the γ-amino acid VI is:
 (i) achiral; and/or 
 (ii) gabapentin; and/or 
 (iii) a mixture of a chiral γ-amino acid VI; and/or 
 (iv) a racemic mixture of a chiral γ-amino acid VI; and/or 
 (v) racemic pregabalin; and/or 
 (vi) a mixture of a chiral γ-amino acid VI, and wherein the process further comprises the step of resolving the mixture of the chiral γ-amino acid VI to provide an enantiomerically pure or enantiomerically enriched stereoisomer of the γ-amino acid VI; and/or 
 (vii) a mixture of a chiral γ-amino acid VI, and wherein the process further comprises the step of resolving the mixture of the chiral γ-amino acid VI to provide enantiomerically pure or enantiomerically enriched pregabalin; and/or 
 (viii) obtained substantially free of lactam impurity. 
 
     
     
         96 . A process for the preparation of pregabalin or racemic pregabalin comprising:
 (a) reaction of isovaleraldehyde with nitromethane to form 2-hydroxy-4-methyl-1-nitro-pentane;   (b) conversion of 2-hydroxy-4-methyl-1-nitro-pentane to 3-nitromethyl-5-methyl-hexanoic acid; and   (c) conversion of 3-nitromethyl-5-methyl-hexanoic acid to pregabalin or racemic pregabalin.   
     
     
         97 . A process according to  claim 96 , wherein:
 (i) a carbanion of nitromethane is generated in step (a) with a base; and/or   (ii) a carbanion of nitromethane is generated in step (a) with a base, wherein the base is used in a catalytic amount; and/or   (iii) a carbanion of nitromethane is generated in step (a) with an alkali metal alkoxide or an alkali metal hydroxide; and/or   (iv) a carbanion of nitromethane is generated in step (a) with sodium methoxide; and/or   (v) step (a) is carried out in an ether solvent; and/or   (vi) step (a) is carried out in an ether solvent selected from tetrahydrofuran, diisopropyl ether, tert-butyl methyl ether, diethyl ether, or mixtures thereof; and/or   (vii) step (a) is carried out in tetrahydrofuran.   
     
     
         98 . A process according to  claim 96 , wherein step (b) comprises converting the hydroxy group of 2-hydroxy-4-methyl-1-nitro-pentane to a leaving group and displacing said leaving group with a dialkyl malonate anion, followed by hydrolysis and decarboxylation to afford 3-nitromethyl-5-methyl-hexanoic acid. 
     
     
         99 . A process according to  claim 98 , wherein:
 (i) the leaving group is a halo group, a sulfonate ester group or a carboxylic ester group; and/or   (ii) the leaving group is a trifluoroacetate group; and/or   (iii) step (b) comprises generating the dialkyl malonate anion with an alkali metal alkoxide base, optionally in combination with an alkali metal carbonate; and/or   (iv) step (b) comprises generating the dialkyl malonate anion with an alkali metal alkoxide base, optionally in combination with sodium carbonate; and/or   (v) step (b) comprises generating the dialkyl malonate anion with sodium methoxide, optionally in combination with an alkali metal carbonate; and/or   (vi) step (b) comprises generating the dialkyl malonate anion with sodium methoxide, optionally in combination with sodium carbonate; and/or   (vii) the dialkyl malonate is dimethyl malonate; and/or   (viii) step (b) comprises hydrolysis and decarboxylation using an organic or mineral acid in the presence of water; and/or   (ix) step (b) comprises hydrolysis and decarboxylation using hydrochloric acid in the presence of water.   
     
     
         100 . A process according to  claim 96 , wherein step (c) comprises:
 (i) catalytic hydrogenation; and/or   (ii) catalytic hydrogenation, wherein the hydrogenation catalyst is selected from Pd/C, Pt/C or PtO 2 ; and/or   (iii) catalytic hydrogenation, wherein the hydrogenation catalyst is Pd/C.   
     
     
         101 . A process according to  claim 96 , wherein:
 (i) racemic pregabalin or pregabalin is obtained substantially free of lactam impurity; and/or   (ii) the process further comprises the step of resolving racemic pregabalin to form pregabalin; and/or   (iii) enantiomerically enriched or enantiomerically pure pregabalin is obtained.   
     
     
         102 . γ-Amino acid VI, when prepared by a process according to  claim 86 . 
     
     
         103 . γ-Amino acid VI: 
       
         
           
           
               
               
           
         
       
       substantially free of lactam impurity, wherein R′ and R″ are independently hydrogen or an alkyl group, or both R′ and R″ together with the carbon atom to which they are attached form a cyclic alkyl group. 
     
     
         104 . A γ-amino acid VI according to  claim 102 , wherein the γ-amino acid is enantiomerically pure or enantiomerically enriched. 
     
     
         105 . A γ-amino acid VI according to  claim 103 , wherein the γ-amino acid is enantiomerically pure or enantiomerically enriched. 
     
     
         106 . Racemic pregabalin, enantiomerically pure pregabalin or enantiomerically enriched pregabalin, when prepared by a process according to  claim 96 . 
     
     
         107 . Racemic pregabalin, enantiomerically pure pregabalin or enantiomerically enriched pregabalin, substantially free of lactam impurity. 
     
     
         108 . A pharmaceutical composition comprising a γ-amino acid VI according to  claim 102 . 
     
     
         109 . A pharmaceutical composition comprising a γ-amino acid VI according to  claim 103 . 
     
     
         110 . A pharmaceutical composition comprising pregabalin according to  claim 106 . 
     
     
         111 . A pharmaceutical composition comprising pregabalin according to  claim 107 . 
     
     
         112 . A method of treating or preventing epilepsy, pain, neuropathic pain, cerebral ischemia, depression, psychoses, fibromyalgia or anxiety, the method comprising administering to a patient in need thereof a therapeutically or prophylactically effective amount of a γ-amino acid VI according to  claim 102 . 
     
     
         113 . A method of treating or preventing epilepsy, pain, neuropathic pain, cerebral ischemia, depression, psychoses, fibromyalgia or anxiety, the method comprising administering to a patient in need thereof a therapeutically or prophylactically effective amount of a γ-amino acid VI according to  claim 103 . 
     
     
         114 . A method of treating or preventing epilepsy, pain, neuropathic pain, cerebral ischemia, depression, psychoses, fibromyalgia or anxiety, the method comprising administering to a patient in need thereof a therapeutically or prophylactically effective amount of pregabalin according to  claim 106 . 
     
     
         115 . A method of treating or preventing epilepsy, pain, neuropathic pain, cerebral ischemia, depression, psychoses, fibromyalgia or anxiety, the method comprising administering to a patient in need thereof a therapeutically or prophylactically effective amount of pregabalin according to  claim 107 . 
     
     
         116 . 2-Hydroxy-4-methyl-1-nitro-pentane. 
     
     
         117 . A compound of formula IVa: 
       
         
           
           
               
               
           
         
       
       wherein R is independently an alkyl group. 
     
     
         118 . A compound according to  claim 117 , wherein R is:
 (i) independently a methyl, ethyl, propyl or butyl group; and/or   (ii) a methyl group.   
     
     
         119 . 2-Carbomethoxy-3-nitromethyl-5-methyl-hexanoic acid methyl ester.